Administration of therapeutic radionuclides that are targeted to specific tumor cells has been used against a variety of tumors. Targeted radionuclide therapy in which radionuclides contained within particle-based carrier moiety systems emit ionizing radiation that is absorbed by target cancer cells has significant potential for personalized cancer therapies. The targeting agent and the absorbed radiation dose delivered by radionuclide-containing particles can be tailored to the individual patient. If the tumor uptake of the radionuclide-containing particles can also be assessed through high-resolution imaging, then treatment planning and dosimetric modeling can be used to determine the best combination of radionuclide and targeting agent for treating the tumor while sparing non-cancerous tissues. This can be followed by adaptive radiotherapy in which molecular imaging with specific targeting agents may allow clinicians to evaluate the response to radionuclide therapy and adjust subsequent treatments to the altered status of the tumor cells resulting from changes in the receptor target populations on tumor cells. The flexibility of this approach makes particle-based targeted radionuclide therapy an attractive approach for cancer treatment.
According to the National Academies Collection, reports on Targeted Radionuclide Therapy that are funded by NIH reveal that there are currently four targeted radiotherapeutics approved by the FDA for human use, all of which employ beta-emitting radionuclides. Committee on State of the Science of Nuclear Medicine, National Research Council, Targeted Nucleotide Therapy, in ADVANCING NUCLEAR MEDICINE THROUGH INNOVATION, at 4.1 (National Academies Press) (2007). These include monoclonal antibodies labeled with 90Y (Zevalin®; Spectrum Pharmaceuticals, Inc., Hendersen, Nev.) or 131I (Bexxar®; GlaxoSmithKline, Philadelphia, Pa.) for the treatment of B-cell lymphoma and related cancers. Excellent clinical results have been observed with these agents (overall response rate of 60-80% and complete response rates of 20-40% for patients with relapsed, recurrent, or refractory indolent B-cell lymphoma). AETNA, INC., CLINICAL POLICY BULLETIN: RADIOIMMUNOTHERAPY FOR NON-HODGKIN'S LYMPHOMA: IBRITUMOMAB TIUXETAN (ZEVALIN) AND TOSITUMOMAB (BEXXAR) (2011). This is similar to the response rate obtained with multiple cycles of conventional chemotherapy, but with a much lower incidence of toxicity. The other FDA-approved radiotherapeutics are 153Sm-EDTMP (Quadramet®; EUSA Pharma (USA), Inc., Langhorne, Pa.) and 89Sr chloride (Metastron®; GE Healthcare, Buckinghamshire, UK) for palliation of bone metastases. In addition, a non-targeted radiotherapeutic agent, Chromic [32P] phosphate (Phosphocol®; Mallinckrodt, St. Louis, Mo.) has been administered via intraperitoneal (i.p.) injection as a palliative treatment of ovarian cancer. Spencer et al., Intraperitoneal P-32 after negative second-look laparotomy in ovarian carcinoma, CANCER 63:2434 (1989). There are a number of other radiotherapeutic agents in the preclinical and clinical stages of research that use beta-emitter radionuclides such as holmium-166 (166Ho).
166Ho is an attractive candidate for use as a therapeutic radionuclide because of its relatively short half-life (26.8 h), which allows for greater control of dosage, time of exposure, etc., and because it emits both high energy beta particles and gamma rays (6.6% photon yield), which allows it to be used for both radioablation and nuclear imaging (e.g., its distribution may to be quantified and imaged after administration). Furthermore, 166Ho's high attenuation coefficient and paramagnetic properties allow it be visualized using x-ray computed tomography (CT) and magnetic resonance imaging (MRI).
The present invention addresses concerns regarding the handling of large amounts of radioactivity during the preparation, storage and transport of therapeutic radionuclides by providing a stable activatable particle that may be produced in a non-radioactive state and subsequently activated to produce a radiotherapeutic agent. Because the stable activatable particles are manufactured in a non-radioactive state, careful quality control measures may be employed (to ensure proper particle size distribution, for example) and FDA manufacturing guidelines may be adhered to without the constraints imposed by the handling of radioactive materials.